Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory and procalcification status within the arterial wall, remain unknown. [unreadable] In this study, our results first demonstrate an age-associated increase of calpain-1 gene transcripts, protein levels and activity in the old aortic wall; increased Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro; the Ang II mediated age-associated increased MMP2 activity, is blocked by calpain inhibitor 1 or CAST, indicating that calpain activity is required for MMP activation by Ang II treatment. An increase in old VSMC migratory capacity is mimicked in young VSMC by over-expression of calpain-1. Collectively, these findings point to increased calpain-1 activity, as a central component of the exaggerated Ang II signaling pathway, which is involved in age-associated arterial remodeling. Thus, Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration.[unreadable] Furthermore, age-associated arterial alterations are characterized both by a shift of VSMC from a contractile to synthetic phenotype, i.e., cytoskeleton restructuring and enhancement of migratory capability, and extracellular matrix remodeling (ECM), ie., collagen types I and III, which could be degenerated by proteases and become immature collagen to form a procalcification niche. Our recent study indicates that calpain-1, increases within VSMC; and orchestrates an angiotensin II cascade which mediates a VSMC phenotype shift within the aged aortic wall, and plays an important role in generating arterial matrix alterations that lead to procalcification. Our results show that over-expression of ectopic calpain-1 by a recombinant adenovirus harboring full length cDNA (pAd/CANP1) in young VSMC increased Col I and III up to the levels of untreated old control cells. Further, over-expression of calpain-1 in young VSMC decreases the counter-calcification molecules osteopontin (OPN) and osteonectin (ON), which mimics aging. In contrast, young VSMC infected with recombinant adenovirus containing calpastatain cDNA (pAd/CAST), an endogenous inhibitor of calpain), increases OPN and ON. An age-associated increase of calpain-1 activity within VSMCs results in enhanced collagen production and reduced counter-calcification molecules, favoring a procacification status, which is a potential molecular mechanism of arterial matrix remodeling with aging. Thus, targeting calpain-1 is a potential approach to delay or reverse the age-associated arterial pro-inflammation and -calcification state that is also associated with diseases such as hypertension, atherosclerosis, and stroke.